Pr Glaucoma is a neurodegenerative disease in which there is specific loss of retinal ganglion cells (RGCs). Current management is directed at lowering intraocular pressure (IOP), through the use of eye drops, laser treatment, and/or operative surgery. Although such treatment can be effective, sufficient IOP lowering cannot always be safely achieved, and sometime even with significant IOP lowering there still can be progression of optic nerve damage. In an effort to complement IOP-based therapy, efforts have been made to develop neuroprotective therapies that directly act to preserve RGC health and function. However, despite important laboratory advances, neuroprotection-based treatment approaches for glaucoma have not yet made it to the clinic. In order to help advance toward a clinically viable neuroprotective strategy, we have been pursuing a variety of approaches to identify novel drug targets and molecular pathways that could be used to promote RGC survival in glaucoma and other optic neuropathies. In a preliminary set of studies we have demonstrated the feasibility of performing an RNAi screen with primary cultures of murine RGCs to identify genes that modulate RGC survival. In this R21 application we propose to further optimize this technology, use it to perform a whole genome siRNA screen, and then validate the identified hits by testing their activity in vivo using an optic nerve crush model of optic nerve injury. PUBLIC HEALTH RELEVANCE: Vision loss from glaucoma is caused by the death of retinal ganglion cells (RGCs), the nerve cells in the retina that carry vision from the eye to the brain. We are using RNA interference-based approaches to try to better understand the signals that trigger RGCs to die. This work will hopefully identify new drug targets that could be used to reduce or prevent RGC death and vision loss, and thereby lead to novel treatment strategies for glaucoma and other optic neuropathies.